Over the years, a number of landmark clinical studies on the management of breast cancer have been published, sharping how patients are treated today.
Breast cancer is a disease in which there is uncontrolled growth of breast cells. It’s estimated that approximately 1 in 8 U.S. women will develop invasive breast cancer over the course of her lifetime and just under 40,000 women will die from the disease in 2018.
Studies suggest that breast cancer death rates have been decreasing since 1989 with the largest decrease in women under 50 years of age. These decreases are believed to be the result of treatment advances, earlier detection through screening, and increased awareness.1
Over the years, a number of landmark clinical studies on the management of breast cancer have been published, sharpening how patients are treated today. Here are 4 that every pharmacist should know about. We will cover 4 more studies in a second article.
1. SABP P-1 (1998)2
Tamoxifen is a selective estrogen receptor modulator (SERM) that was first approved by the FDA in 1977 for use in women with breast cancer. Although tamoxifen’s benefit had been well-established by the 1990s, the role of the medication for breast cancer prevention had not yet been fully studied.
To further explore the primary prevention effects of tamoxifen, more than 13,000 women aged 35 years and older were randomly assigned in a double-blind manner to receive placebo or tamoxifen 20 mg/day for 5 years. To be eligible for the trial, participants had to have been at increased risk for breast cancer due to age 60 years or older or between the ages of 35 and 59 years with a 5-year predicted risk for breast cancer of at least 1.66% or had a history of lobular carcinoma in situ. The primary endpoint was the incidence of invasive breast cancer.
Study results showed there was a significant 49% reduction in the overall risk of invasive breast cancer in the tamoxifen group as compared to placebo (89 vs 175 cases; p< 0.00001). Tamoxifen also reduced the risk of noninvasive breast cancer by 50% and the occurrence of estrogen receptor (ER)-positive tumors by 69%. No difference was seen in the occurrence of ER-negative tumors. Notably, participants who received tamoxifen had a 2.53 times greater risk of developing an invasive endometrial cancer (95% CI: 1.35—4.97) than did women who received placebo. This increased risk was predominantly in women aged 50 years or older. Additionally, pulmonary emboli were observed in almost 3 times as many women in the tamoxifen group as in the placebo group (RR = 3.01; 95% CI: 1.15–9.27). There was a numerically lower number of deaths in the tamoxifen group compared to placebo, although it did not reach statistical significance (RR = 0.81; 95% CI: 0.56–1.16).
Following the study’s results, the FDA approved tamoxifen for primary breast cancer prevention in high risk women.
In high risk women, tamoxifen decreases the incidence of invasive and noninvasive breast cancer, but also increases the risk of endometrial cancer and pulmonary embolism.
2. MORE, CORE (2004)3,4
Raloxifene is another SERM that was approved by the FDA in 1997 for the prevention of postmenopausal osteoporosis and in 2007 to reduce the risk of breast cancer in certain women. Its approvals were based on results from the MORE and CORE trials.
MORE was a multicenter, randomized, placebo-controlled trial that enrolled 7705 postmenopausal women with osteoporosis, aged 31 to 80 years, to receive raloxifene 60 mg/day, 120 mg/day, or placebo. The primary endpoint was the effect of incident vertebral fractures and bone mineral density; however, the incidence of breast cancer was assessed as a secondary safety endpoint. After 4 years, raloxifene 60 mg reduced the incidence of all breast cancers by 62% as compared with placebo (HR = 0.38; 95% CI: 0.22-0.67). Raloxifene also reduced the incidence of invasive breast cancer by 71%, compared with placebo (HR = 0.29; 95% CI: 0.15, 0.56), which was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer.
CORE was a follow-up study that examined the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer. Treatment assignments from the MORE trial were carried forward to this study. Study results showed that raloxifene 60 mg reduced the incidence of invasive breast cancer by 56% compared with placebo (HR = 0.44; 95% CI: 0.24-0.83), which was driven by a large decrease in the incidence of ER-positive invasive breast cancer. In both studies there were no statistically significant differences in incidence of noninvasive breast cancer between the raloxifene and placebo groups. No new safety concerns related to raloxifene therapy were identified during the study.
Raloxifene reduces the risk of invasive breast cancer in postmenopausal women with osteoporosis.
3. ATAC (2002)5
Historically, tamoxifen had been the treatment of choice in the adjuvant setting for women with hormone-sensitive disease. Third-generation aromatase inhibitors, including anastrozole, became available in the mid-1990s, initially for the treatment of advanced breast cancer in postmenopausal women for whom tamoxifen therapy fails.
ATAC was conducted to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and in combination. Eligible participants were postmenopausal women with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. Over 9000 participants were randomized in a 1:1:1 ratio to receive anastrozole 1mg/day, tamoxifen 20 mg/day, or the combination of anastrozole plus tamoxifen. The primary endpoints were disease-free survival and occurrence of adverse events. The median follow-up was 33.3 months.
Analysis of the data found there was a significant 17% reduction in disease-free survival at 3 years in the anastrozole group as compared to tamoxifen (HR = 0.83; 95% CI: 0.71—0.96; p=0·013). The improvement in disease-free survival with anastrozole was seen in the subgroup of ER-positive patients, but not the ER-negative patients. Results with the combination group were not significantly different from those with tamoxifen alone. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen; when compared with tamoxifen, the odds were reduced by 58% (OR = 0.42, 95% CI: 0.22–0.79; p=0·007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, and hot flashes, while tamoxifen was better tolerated with respect to musculoskeletal disorder and fractures.
A follow-up study of long-term outcomes found that after a median follow-up of 10 years anastrozole continued to demonstrate superior efficacy and safety over tamoxifen.
Anastrozole is more effective than tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.
4. Intergroup Exemestane Study (2004)6
Exemestane is an aromatase inhibitor FDA approved in 2005 based on results from the Intergroup Exemestane Study. With 5 years of tamoxifen therapy being standard adjuvant treatment for postmenopausal women with ER—positive breast cancer, researchers looked for alternative treatment regimens in women who relapse after tamoxifen therapy.
The study was designed as a randomized, double-blind, multinational trial to determine whether after 2 to 3 years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the 5 years of treatment. In total, 4742 patients enrolled in the study and were followed-up for a median of 30.6 months. The primary end point was disease-free survival.
Study results showed a significant 32% reduction in the primary endpoint with exemestane as compared to tamoxifen (HR = 0.68; 95% CI: 0.56-0.82; p<0.001) corresponding to an absolute benefit in terms of disease-free survival of 4.7%. Survival free of distant disease was also better in the exemestane group however when looking at overall mortality there was no statistically significant difference between the groups. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (p=0.04). Thromboembolic events and gynecologic symptoms were recorded more frequently in the tamoxifen group while exemestane was associated with a higher incidence of arthralgia, diarrhea, and fractures.
Switching patients to adjuvant treatment with exemestane after 2 to 3 years of tamoxifen therapy is associated with better disease-free survival.